Genome wide association (GWA) scans have allowed an assessment of disease pathways in patients with MS and Tl D based on the unbiased identification of gene variants. We will investigate these allelic variants and their pathways that are both common (CD226/TIGIT) and unique (CTLA4-T1D and CD6-MS) to these diseases. The central role of Thi7 and regulatory T cells in MS has recently been elucidated, and as part of this PPG we demonstrated a loss of regulatory T cell function in MS. We also discovered that increasing the strength of signal through the TCR influences the plasticity of CD4+CD25high Tregs to become Thi7 cells. These data have led to the underlying hypothesis that allelic variants in multiple costimulatory pathways lead to a shift from regulatory to inflammatory T cell function. We will explore the costimulatory pathways identified from GWA scans in relationship to Treg and Thi7 function, investigating the CTLA-4/CD28, CD226/TIGIT, and CD6 pathways. Specifically, we will determine: 1) the role of sCTLA4 in the function and plasticity of human Treg populations in close collaboration with Wicker/Todd; 2) how CD6 MS-risk alleles that induce splice variants alter the CD6 costimulatory pathway, investigating the hypothesis that alterations in the CD6 isoforms affect binding to its ligand results in changes influencing the function of Tri and Tregs in patients with MS; and 3) how the CD226/TIGIT costimulatory pathway modulate Treg and Thi 7 function in human autoimmune disease. Our preliminary data demonstrate a lack of TIGIT expression on Thi7 cells while blocking CD226 corrects defects in Treg function in MS leading us to hypothesize that allelic variants in the CD226/TIGIT pathways influence Th17 and Treg function. We will directly examine whether defects in Treg suppression in MS and hyperactivation of monocytes in patients with T1D are corrected by promoting TIGIT signaling. In summary, it is clear that genetic risk to develop autoimmune disease is due to many common and rare allelic variants each with a small effect that together lead to organ specific inflammation in response to undefined environmental challenges. We will apply new tools to examine how genetic variants lead to the heightened immune responses observed in patients with autoimmune diseases.